Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFNγR1 signaling and IDO expression
Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFNγR1 signaling and IDO expression
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DOI：
10.1182/blood-2007-04-083162
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Mueller, Ingo
中科院分区：
文献类型：
--
作者：
Gieseke, Friederike;Schuett, Burkhardt;Mueller, Ingo
多能间充质基质细胞 (MSC) 在体外抑制大多数（如果不是全部）外周血单核细胞 (PBMC) 亚群的增殖、辅助细胞和效应子功能。人们普遍认为该分子机制暗示干扰素γ (IFNγ) 诱导的吲哚胺2,3-双加氧酶表达导致色氨酸降解(1130)。然而，IDO 抑制剂无法恢复每种情况下 PBMC 的增殖。此外，具有 IFN γ 受体 1 (R1) 缺陷的人 MSC 抑制 HLA 不匹配的 PBMC 增殖的程度与对照 MSC 相似。与健康的 MSC 相比，IFN γ R1 缺陷的 MSC 没有显示出可检测到的 IDO mRNA，无论是在重组人 IFN γ 不存在或存在的情况下，还是与 HLA 不匹配的 PBMC 共培养时。基于基因表达谱，我们能够证明胰岛素样生长因子（IGF）结合蛋白有助于间充质干细胞的抑制机制。总而言之，人类 MSC 在缺乏 IFN γ R1 信号传导和 IDO 的情况下发挥重要的免疫调节功能，部分原因是 IGF 结合蛋白。
Multipotent mesenchymal stromal cells (MSCs) inhibit proliferation, helper, and effector functions in most if not all peripheral blood mononuclear cell (PBMC) subpopulations in vitro. The molecular mechanism is widely thought to imply tryptophan degradation by the interferon-gamma (IFN gamma)-induced expression of indoleamine 2,3-dioxygenase (1130). However, IDO inhibitors were not able to restore proliferation of PBMCs in each case. Moreover, human MSCs with an IFN gamma receptor 1 (R1) defect inhibited proliferation of HLA-mismatched PBMCs to a similar extent as control MSCs. In contrast to healthy MSCs, IFN gamma R1-deficient MSCs showed no detectable mRNA for IDO-neither in the absence nor in the presence of recombinant human IFN gamma, nor in coculture with HLA-mismatched PBMCs. Based on gene expression profiling, we were able to show that insulin-like growth factor (IGF)-binding proteins contribute to the inhibitory mechanism of MSCs. Taken together, human MSCs exert important immunomodulatory functions in the absence of IFN gamma R1 signaling and IDO, partially accounted for by IGFbinding proteins.